The purpose of this proposal is to evaluate the efficacy of the opioid antagonists, naloxone and its oral analogue, naltrexone, in the treatment of Alzheimer's disease (AD). These antagonists have been shown to affect memory in animal models. They have also been shown to exert direct effects on hippocampal excitation. Recent research has provided an explanation for these behavioral effects by demonstrating naloxone binding diffusely throughout the cortex, as well as in the hippocampus and in limbic regions. Naloxone has reversed ischemic deficits in humans as well as in animals. Recent pilot trials in AD patients have evidenced a positive behavioral and psychometric response following 1 mg of naloxone I.V. In this project, we propose to evaluate the efficacy of the opiate antagonists naloxone and naltrexone in the treatment of AD patients, in double-blind controlled trials. In Trial 1, we propose to determine the short-term effects of 1 mg, 5 mg, and 10 mg of naloxone, administered intravenously, in comparison with placebo injections in 20 patients with AD. The study will be conducted utilizng a double-blind, multiple dose, randomized sequence, crossover design. Patients will receive behavioral, psychometric, and laboratory evaluations following each injection. In Trial 11, we intend to evaluate the efficacy of 100 mg of naltrexone, administered orally, on 20 AD patients. A double-blind, placebo controlled crossover design will be followed with 1-week placebo washout periods between each 4-week treatment phase (1-4-1-4). Patients will receive clinical psychometric, and laboratory evaluations on a regular basis throughout the study. Since there are presently no clinically effective treatments for AD, any positive results of the study would be of potential significance.